Loss of Insulin ‐like Growth Factor‐1 Signaling in Astrocytes Disrupts Glutamate Handling

In this study, we examined whether IGF‐1 acts through its cognate receptor, IGFR, to alter astrocytic glutamate handling. We utilized both small molecule IGFR inhibitors and Cre‐driven genetic approaches to reduce IGFR in vivo and in cultured rodent astrocytes. W hen IGFR was knocked out of primary astrocytes derived fromigfrf/f mice using AAV5 ‐CMV‐Cre, significant reductions in glutamate uptake were observed. Similarly, inhibition of IGFR with picropodophyllotoxin for 2 hours, as well as 24 hours, reduced glutamate uptake in vitro. Mechanistically, short‐term inhibition of IGFR resulted in a significant decrease in glutamate tran sporter availability on the cell surface, as assessed by biotinylation. Long‐term inhibition of IGFR led to significant reductions in mRNA expression of glutamate transport machinery, as assessed with qPCR. Reduced glutamate transporter mRNA was also observed in the brains of astrocyte‐specific IGFR deficient mice, three to four months after knock‐out was induced with tamoxifen. Interestingly, long‐term IGF‐1 inhibition also resulted in an increase in adenosine triphosphate (ATP)‐stimulated glutamate release, though no change in ATP‐stimluated calcium flux was observed nor were a ny changes in purinergic receptor protein expression. Together, these data suggest that reduced IGF‐1 signaling will favor an accumulation of extrasynaptic glutamate, which may contribute to neurodegeneration in disease states where IGF‐1 leve...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: Original Article Source Type: research